EP1438299B1 - Agent chelatant bifonctionnel pour l'actinium - Google Patents

Agent chelatant bifonctionnel pour l'actinium Download PDF

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Publication number
EP1438299B1
EP1438299B1 EP02772300A EP02772300A EP1438299B1 EP 1438299 B1 EP1438299 B1 EP 1438299B1 EP 02772300 A EP02772300 A EP 02772300A EP 02772300 A EP02772300 A EP 02772300A EP 1438299 B1 EP1438299 B1 EP 1438299B1
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EP
European Patent Office
Prior art keywords
chelate
nhco
actinium
ligand
metal
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EP02772300A
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German (de)
English (en)
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EP1438299A1 (fr
Inventor
Ali Ouadi
Jean-François GESTIN
Christos Apostolidis
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European Union Represented By European Co
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European Community EC Belgium
European Economic Community
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to bifunctional chelating agents and more particular to bifunctional polyaza polycarboxylic or polyphosphonic macrocycles ligands a method of synthesis of these products and their uses.
  • WO 9 520 580 and Chem. Ber./Red. (1997), 130(2), 267 disclose macrocyclic octaaza compounds.
  • WO 0 059 896 discloses actinium complexes of hexaazacyclohexadecane compounds.
  • An object of the invention is to provide more effective bifunctional chelating agents for metals especially actinides and lanthanides.
  • the present invention relates to actinium chelates of a ligand of formula: wherein n is an integer from 1 to 5 Y is -CO 2 H or -PO 3 H 2 T represents -X or -phenyl-X, wherein X represents -NO 2 , -NH 2 , -NCS, -NHCOCH 2 -Z, -NHCO-W-COCNHS, -NH-Q, -NHCS-Q, -NHCOCH 2 -Q, or -NHCO(CH 2 ) m -Q where Q is a hapten chosen from the group consisting of steroids, enzymes, proteins, monoclonal antibodies, chimeric antibodies, or fragments thereof or any activated linker ready for coupling reaction, W is -(CH 2 ) m - m is an integer from 1 to 10 Z is chloride, bromide or iodine.
  • X represents -NH-Q, -NHCS-Q, -NHCOCH 2 -Q, or -NHCO(CH 2 ) m -Q
  • Q is a hapten chosen from the group consisting of steroids, enzymes, proteins, monoclonal antibodies, chimeric antibodies, humanised antibodies or fragments thereof
  • the resulting ligand is also called a ligand-hapten conjugate.
  • the invention also includes according to a preferred embodiment, a metal chelate of the ligand as described above wherein the metal is actinium-225 ( 225 Ac).
  • the present invention also includes the method of using the metal chelates of the ligand-hapten conjugate possessing a linking group wherein the chelate as a therapeutic or diagnostic agent.
  • such ligands are useful for radiolabeling proteins with radioactive metals, and can consequently be utilised with respect to radioimmunoimaging and/or radioimmunotherapy.
  • the present ligand-hapten conjugates firmly link actinium to proteins, minimise metal release and permit high selective delivery of metals to targeted sites in vivo. This is especially true for the actinium complexation metal chelate protein conjugates.
  • Immunotherapy with radiolabelled antibodies allows fairly specific targeting of certain cancers (see e.g. Couturier, O. et al. "Validation of 213-Bi-alpha radioimmunotherapy for multiple myeloma" in Clin. Cancer. Res., Vol. 5, pp. 3165-3170, 1999 ; Huneke, R. B., et al. in "Effective alpha-particle-mediated radioimmunotherapy of murine leukemia” in Cancer Res., Vol. 52, pp. 5818-5820, 1992 ; Kennel, S. J. et al. "Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi” in Br. J . Cancer, Vol.
  • This technique is based on the use of radionuclides associated to antibodies or peptides that are specific of antigens expressed on the tumor cells.
  • BCA bifunctional chelating agents
  • 225 Ac which is an alpha emitter, is a good candidate for such applications as described by Kaspersen, F. M. et al. "Cytotoxicity of 213Bi- and 225Ac-immunoconjugates" in Nucl. Med. Commun., Vol. 16, pp. 468-476, 1995 .
  • the very short range ( ⁇ 100 ⁇ m) of ⁇ -particles and the high energy transfer allows efficient destruction of tumor cells whereas normal cells are relatively spared.
  • Chelators that can hold radioactive metals with high stability' under physiological conditions are essential to avoid excessive radiation damage to non-target cells.
  • bifunctional chelating agents allow different applications; it can be used to bind 225 Ac to any biological or non-biological structures for any applications.
  • chelating agents can be used non-associated to a vector as a detoxication chelating agent or using the natural tropism of the complex.
  • This chelating agent can also be used grafted on a chromatographic column in order to purify or concentrate any solutions containing 225 Ac.
  • Figure 1 represents a scheme for the preparation of a substituted 1,4,7,10,13,16,19,22-octa(2-carboxymethyl)-octaaazacyclotetracosane ligand (8).
  • Triethylamine (22 mmol) was added to a suspension of 4-nitrophenylalanine methyl ester hydrochloride (1) (21 mmol) in THF (50 ml). The mixture was stirred at room temperature for one hour, the triethylamine hydrochloride was filtered off, and the filtrate concentrated to yellow oil. The oil was dissolved in dry THF (50 ml) and to this solution was added triethylamine (60 mmol) and methylbromoacetate (60 mmol), the solution was stirred at room temperature under nitrogen atmosphere for 3 hours, after which the precipitate was filtered off and the filtrate concentrated on vacuum. The residue was dissolved in ethylacetate, washed with H 2 O, dried (MgSO 4 ) and concentrated on vacuum to give yellow oil.
  • the column was eluted consecutively with 0.5 M HCl and with water until the eluent was neutral and finally with 0.5 M aqueous ammonia solution. Alkaline fractions were collected, and the water was removed on vacuum

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Claims (8)

  1. Chélate métallique bifonctionnel du ligand, dans lequel le métal est l'actinium, ledit ligand comprenant
    Figure imgb0004
     où
    n représente un entier de 1 à 5,
    Y représente un groupe -CO2H ou un groupe -PO3H2,
    T représente un groupe -X ou un groupe -phényle-X, dans lequel
    X représente un groupe -NO2, un groupe -NH2, un groupe -NCS, un groupe -NHCOCH2-Z, un groupe -NHCO-W-COCNHS, un groupe -NH-Q, un groupe -NHCS-Q, un groupe -NHCOCH2-Q ou un groupe -NHCO(CH2)m-Q où Q représente un haptène choisi parmi le groupe constitué par des stéroïdes, des enzymes, des protéines, des anticorps monoclonaux, des anticorps chimères ou leurs fragments ou encore n'importe quel lieur activé prêt pour une réaction de couplage,
    W représente un groupe -(CH2)m-,
    m représente un entier de 1 à 10,
    Z représente un chlorure, un bromure ou un iodure.
  2. Chélate métallique selon la revendication 1, dans lequel le métal est l'actinium-225 (225Ac).
  3. Chélate métallique selon l'une quelconque des revendications 1 à 2, dans lequel X représente un groupe -NHCO-W-COCNHS, un groupe -NH-Q, un groupe -NHCS-Q, un groupe -NHCOCH2-Q ou un groupe -NHCO(CH2)m-Q où Q représente un haptène choisi parmi le groupe constitué par des stéroïde, des enzymes, des protéines, des anticorps monoclonaux, des anticorps chimères ou leurs fragments ou encore n'importe quel lieur activé prêt pour une réaction de couplage
  4. Chélate métallique selon l'une quelconque des revendications 1 à 3, à utiliser comme agent thérapeutique ou diagnostique
  5. Utilisation du chélate métallique selon l'une quelconque des revendications 1 à 3, pour la préparation d'un médicament à utiliser comme agent thérapeutique ou diagnostique dans la radioimmunoimagerie et/ou dans la radioimmunothérapie
  6. Utilisation du ligand selon la revendication 1 ou du chélate selon l'une quelconque des revendications 1 à 3, à titre d'agent d'extraction dans le procédé de séparation d'actinides et de lanthanides mineurs dans des déchets nucléaires ou pour séparer des groupes spécifiques de métaux dans des déchets fortement radioactifs
  7. Utilisation du ligand selon la revendication 1 ou du chélate selon l'une quelconque des revendications 1 à 3, à des fins de greffage sur une colonne chromatographique dans le but de concentrer ou de purifier n'importe quelle solution contenant de l'actinium
  8. Utilisation dans une structure non biologique du ligand selon la revendication 1 ou du chélate selon l'une quelconque des revendications 1 à 3, pour la désintoxication à titre de complexe d'agent de chélation des actinides et des lanthanides dans des structures non-biologiques
EP02772300A 2001-09-17 2002-09-13 Agent chelatant bifonctionnel pour l'actinium Expired - Lifetime EP1438299B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
LU90834A LU90834B1 (en) 2001-09-17 2001-09-17 Bifunctional chelating agent for actinium
LU90834 2001-09-17
PCT/EP2002/010306 WO2003024940A1 (fr) 2001-09-17 2002-09-13 Agent chelatant bifonctionnel pour l'actinium

Publications (2)

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EP1438299A1 EP1438299A1 (fr) 2004-07-21
EP1438299B1 true EP1438299B1 (fr) 2010-06-02

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EP02772300A Expired - Lifetime EP1438299B1 (fr) 2001-09-17 2002-09-13 Agent chelatant bifonctionnel pour l'actinium

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US (1) US7045606B2 (fr)
EP (1) EP1438299B1 (fr)
JP (1) JP2005507885A (fr)
AT (1) ATE469890T1 (fr)
AU (1) AU2002337093B2 (fr)
CA (1) CA2458267C (fr)
DE (1) DE60236608D1 (fr)
IL (2) IL160563A0 (fr)
LU (1) LU90834B1 (fr)
NO (1) NO326695B1 (fr)
NZ (1) NZ531301A (fr)
WO (1) WO2003024940A1 (fr)

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Publication number Priority date Publication date Assignee Title
JPH03197468A (ja) * 1989-12-26 1991-08-28 Teijin Ltd 二官能性大環状キレート配位子およびその製造法
DE4403039A1 (de) * 1994-01-28 1995-08-03 Schering Ag Oktaazamakrocyclen, deren Metallkomplexe, Verfahren zu deren Herstellung, diese Komplexe enthaltende Mittel sowie deren Verwendung in Diagnostik und Therapie
WO2000059896A1 (fr) * 1999-03-23 2000-10-12 The United States Of America, Represented By The Secretary, Department Of Health And Human Services 225ac-heha et composes, procedes de synthese et procedes d'utilisation correspondants
LU90544B1 (en) 2000-03-14 2001-09-17 Europ Economic Community Bifunctional chelating agent

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Publication number Publication date
LU90834B1 (en) 2003-03-18
AU2002337093B2 (en) 2008-03-13
US7045606B2 (en) 2006-05-16
NO20040997L (no) 2004-03-09
NO326695B1 (no) 2009-02-02
ATE469890T1 (de) 2010-06-15
CA2458267C (fr) 2011-06-14
EP1438299A1 (fr) 2004-07-21
NZ531301A (en) 2005-10-28
CA2458267A1 (fr) 2003-03-27
IL160563A0 (en) 2004-07-25
WO2003024940A1 (fr) 2003-03-27
DE60236608D1 (de) 2010-07-15
IL160563A (en) 2009-08-03
JP2005507885A (ja) 2005-03-24
US20040242852A1 (en) 2004-12-02

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